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- EMDB-39834: SLC19A2-Pyridoxine inward structure -

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Basic information

Entry
Database: EMDB / ID: EMD-39834
TitleSLC19A2-Pyridoxine inward structure
Map data
Sample
  • Complex: SLC19A3-Thiamine complex
    • Protein or peptide: Thiamine transporter 1
  • Ligand: 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol
KeywordsThiamine transporter / MFS / MEMBRANE PROTEIN
Function / homology
Function and homology information


folic acid transmembrane transporter activity / pyridoxine transport / thiamine-containing compound metabolic process / Vitamin B1 (thiamin) metabolism / thiamine transmembrane transport / thiamine transmembrane transporter activity / thiamine transport / thiamine diphosphate biosynthetic process / transmembrane transport / spermatogenesis ...folic acid transmembrane transporter activity / pyridoxine transport / thiamine-containing compound metabolic process / Vitamin B1 (thiamin) metabolism / thiamine transmembrane transport / thiamine transmembrane transporter activity / thiamine transport / thiamine diphosphate biosynthetic process / transmembrane transport / spermatogenesis / membrane / plasma membrane
Similarity search - Function
Thiamine transporter 1 / Reduced folate carrier / Reduced folate carrier / MFS transporter superfamily
Similarity search - Domain/homology
Thiamine transporter 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsLi PP / Zhu ZN / Wang Y / Gao P / Qu QH
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2024
Title: Substrate transport and drug interaction of human thiamine transporters SLC19A2/A3.
Authors: Peipei Li / Zhini Zhu / Yong Wang / Xuyuan Zhang / Chuanhui Yang / Yalan Zhu / Zixuan Zhou / Yulin Chao / Yonghui Long / Yina Gao / Songqing Liu / Liguo Zhang / Pu Gao / Qianhui Qu /
Abstract: Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine ...Thiamine and pyridoxine are essential B vitamins that serve as enzymatic cofactors in energy metabolism, protein and nucleic acid biosynthesis, and neurotransmitter production. In humans, thiamine transporters SLC19A2 and SLC19A3 primarily regulate cellular uptake of both vitamins. Genetic mutations in these transporters, which cause thiamine and pyridoxine deficiency, have been implicated in severe neurometabolic diseases. Additionally, various prescribed medicines, including metformin and fedratinib, manipulate thiamine transporters, complicating the therapeutic effect. Despite their physiological and pharmacological significance, the molecular underpinnings of substrate and drug recognition remain unknown. Here we present ten cryo-EM structures of human thiamine transporters SLC19A3 and SLC19A2 in outward- and inward-facing conformations, complexed with thiamine, pyridoxine, metformin, fedratinib, and amprolium. These structural insights, combined with functional characterizations, illuminate the translocation mechanism of diverse chemical entities, and enhance our understanding of drug-nutrient interactions mediated by thiamine transporters.
History
DepositionApr 21, 2024-
Header (metadata) releaseJan 8, 2025-
Map releaseJan 8, 2025-
UpdateJan 8, 2025-
Current statusJan 8, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_39834.png

Downloads & links

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Map

FileDownload / File: emd_39834.map.gz / Format: CCP4 / Size: 103 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 300 pix.
= 279.6 Å		0.93 Å/pix.
x 300 pix.
= 279.6 Å		0.93 Å/pix.
x 300 pix.
= 279.6 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.932 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-4.879629 - 4.643675
Average (Standard dev.)0.0006001817 (±0.046803705)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions300300300
Spacing300300300
CellA=B=C: 279.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_39834_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_39834_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : SLC19A3-Thiamine complex

EntireName: SLC19A3-Thiamine complex
Components
  • Complex: SLC19A3-Thiamine complex
    • Protein or peptide: Thiamine transporter 1
  • Ligand: 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol

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Supramolecule #1: SLC19A3-Thiamine complex

SupramoleculeName: SLC19A3-Thiamine complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Thiamine transporter 1

MacromoleculeName: Thiamine transporter 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.432605 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDVPGPVSRR AAAAAATVLL RTARVRRECW FLPTALLCAY GFFASLRPSE PFLTPYLLGP DKNLTEREVF NEIYPVWTYS YLVLLFPVF LATDYLRYKP VVLLQGLSLI VTWFMLLYAQ GLLAIQFLEF FYGIATATEI AYYSYIYSVV DLGMYQKVTS Y CRSATLVG ...String:
MDVPGPVSRR AAAAAATVLL RTARVRRECW FLPTALLCAY GFFASLRPSE PFLTPYLLGP DKNLTEREVF NEIYPVWTYS YLVLLFPVF LATDYLRYKP VVLLQGLSLI VTWFMLLYAQ GLLAIQFLEF FYGIATATEI AYYSYIYSVV DLGMYQKVTS Y CRSATLVG FTVGSVLGQI LVSVAGWSLF SLNVISLTCV SVAFAVAWFL PMPQKSLFFH HIPSTCQRVN GIKVQNGGIV TD TPASNHL PGWEDIESKI PLNMEEPPVE EPEPKPDRLL VLKVLWNDFL MCYSSRPLLC WSVWWALSTC GYFQVVNYTQ GLW EKVMPS RYAAIYNGGV EAVSTLLGAV AVFAVGYIKI SWSTWGEMTL SLFSLLIAAA VYIMDTVGNI WVCYASYVVF RIIY MLLIT IATFQIAANL SMERYALVFG VNTFIALALQ TLLTLIVVDA SGLGLEITTQ FLIYASYFAL IAVVFLASGA VSVMK KCRK LEDPQSSSQV TTS

UniProtKB: Thiamine transporter 1

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Macromolecule #2: 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol

MacromoleculeName: 4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol / type: ligand / ID: 2 / Number of copies: 1 / Formula: UEG
Molecular weightTheoretical: 169.178 Da
Chemical component information

ChemComp-UEG:
4,5-bis(hydroxymethyl)-2-methyl-pyridin-3-ol

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 6
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 157332
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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